| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Administration of monoclonal antibody(mAb) against PD-1,an immune suppressive molecule, exacerbated disease in experimental allergic encephalomyelitis(EAE) induced by immunization with PLP139-151 peptide in SJL/j mice. In addition, administration of mAb against PD-L1 but not PD-L2, a ligand for PD-1, also exacerbated EAE. These results suggest that PD-L1-PD-1 pathway plays a suppressive role in this system. We next examined the role of TRAIL (TNF related apoptosis inducing ligand), also known as other immune suppressive molecule, in the pathogenesis of systemic autoimmune disease. Although neutralization of TRAIL by mAb exacerbated EAE, stimulation of TRAIL receptor by mAb against DR5 slightly but not significantly suppressed autoantibody production and ameliorated lupus nephritis in NZB/W F1 mice. These results indicate that TRAIL/TRAIL receptor system play minor role in the pathogenesis of systemic autoimmunity in NZB/W F1 mice.
Therefore, we focused on the organ-specific autoimmune diseases to investigate the role of immunosuppressive molecules. Autoantigen (type-II collagen(CII))-specific T cells were retrovirally transduced with PD-1,CTLA-4,or TRAIL gene. Collagen-induced arthritis(CIA) mice (a model for rheumatoid arthritis) were treated by the transfer of these modified T cells after the 2^<nd> immunization with CII. We found that all of the treatment efficiently ameliorated CIA. Next we perform in vivo imaging study by the transfer of luciferase-gene transduced T cell. In vivo imaging study revealed that transferred T cells initially accumulated into the lung. Then, autoantigen-non-specific T cells were accumulated into draining lymph node and liver, but not inflamed joints. However, CII-specific T cells efficiently accumulated into inflamed joints. These results strongly suggest that CII-specific immune suppressive molecule-expressing T cell inhibited CIA inflammation locally by homing to and remaining in the inflamed joints.
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